Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-23
2002-11-19
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S305000, C514S281000, C514S345000, C514S346000, C514S347000
Reexamination Certificate
active
06482837
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention in the field of medicinal chemistry, pharmacology and medicine, related to novel compounds, and derivatives of known compounds and methods for their use in the treatment of bladder disease, particularly urinary incontinence, by intravesical instillation.
2. Description of the Background Art
Urinary incontinence afflicts a large and diverse patient population. The United States Department of Health and Human Services Agency for Health Care Policy and Research (AHCPR) reviewed the literature on the incidence of urinary incontinence, the clinical, psychological, and social impact of the disorder, as well as monetary costs to society.
Clinical Practice Guideline for Urinary Incontinence in Adults
(AHCPR 92-0038, 1992; abbreviated “AHCPR 1992”). Estimates vary, but approximately 15% of a randomly selected group of women perceived urinary incontinence as a social or hygienic problem. For noninstitutionalized individuals older than 60, the prevalence ranges from 15 to 30%, with women having twice the prevalence of men. Among those identified, approximately 25% have daily or weekly episodes of incontinence. Among nursing facility residents, the incidence is 50% or greater, with episodes occurring more than once per day. The annual direct costs of care based on 1987 dollars was estimated as $7 billion in the community and $3.3 billion in nursing homes.
Anticholinergic Therapy and the Treatment of Urinary Incontinence
For a detailed description of anticholinergic agents and their use in treating various diseases, see: Faye, W. P., PRINCIPLES OF MEDICINAL CHEMISTRY, Lea and Fibiger, 1989, pp. 328-348; Gilman, A. G. et al., (eds),
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,
8th Edition, Macmillan Publishing Co., New York, 1990, chapter 8, pp. 150-165, both of which references are hereby incorporated by reference herein).
Contraction of the bladder detrusor muscle is mediated by cholinergic muscarinic receptors. Muscarinic receptors are divisible into several subtypes which are distinguishable based on binding of selective ligands. These muscarinic receptor subtypes exist in differing concentrations in different tissues. The M
3
muscarinic receptors predominate in the detrusor muscle, having about a ten-fold greater density than M
1
or M
2
receptor subtypes (Kondo, S. et al.,
Urol. Int
54:150-153, 1995; Kondo, S. et al.,
J. Smooth Muscle Res.
29:63-68, 1993; Shishido, K. et al., 26th Meeting of the International Continence Society.
Neurourol and Urodynamics
15:313-314, 1996 (Abstract #36)). The present invention targets these receptors by administration of novel antimuscarinic agents via a catheter to the bladder to attain prolonged maintenance of bladder control in otherwise incontinent patients.
The drug oxybutynin chloride (
FIG. 1K
) (4-diethylamino)-2-butynyl-&agr;-cyclohexyl-&agr;-hydroxybenzeneacetate HCl; trade name Ditropan®) is the current standard anticholinergic therapeutic agent for urinary incontinence. Relief of symptoms in neurogenic bladder disorders are thought to result from its combined anticholinergic, antispasmodic, and local anesthetic activities. The anticholinergic side-effects limit its acceptability to many patients. In fact, use of oral oxybutynin is frequently discontinued because of the unpleasantness of the side effects (Thuroff et al,
J. Urol.
145:813-817, 1991).
For treatment of detrusor overactivity, AHCPR 1992 (since reissued with minor revisions) recommended oxybutynin at oral doses of 2.5-5 mg, to be taken 3-4 times per day. At the time of agency review, 5 of 6 randomized controlled studies had reported superiority of oxybutynin to placebo. One exception was a study of elderly nursing home residents which used less frequent administration of the drug.
The dose-related anticholinergic side effects of oral oxybutynin include marked xerostomia, dry skin, blurred vision, nausea, and constipation. Severe mouth dryness occurred in 84% of subjects receiving 5 mg/kg four times/day (AHCPR, 1992). Side effects could be minimized by administration of this compound via clean intermittent self-catheterization directly into the bladder (intravesical administration). However, this required at least daily self-catheterization. Better restoration of bladder control required multiple catheter insertions each day. A series of papers reported beneficial effects in different patient groups. The following are representative: Brendler,
J. Urol.
141:1350-1352, 1989; Weese, D. L. et al.,
Urology
41:527-530, 1993; Greenfield, S. P. et al.,
J. Urol.
146:532-534, 1991; Madersbacher, M. et al.,
Paraplegia
29:84-90, 1991).
A double-blind, randomized, placebo-controlled, parallel group study of intravesical oxybutynin was reported at a recent conference (Krishnan, K. R.,
Neurourol and Urodyn.
15:307-308, 1996). There was some systemic absorption of the drug following intravesical administration, but the incidence of adverse side effects was low. However, the difficulty in patients being able to continue a typical intravesical instillation protocol is illustrated by Weese et al. (supra), which reported that instillation of the drug two to three times daily via clean self intermittent catheterization resulted in 21% of the patients dropping out due to inability to tolerate the catheterization or to difficulty in retaining the drug solution in the bladder.
McPherson et al. (U.S. Pat. No. 5,001,160) described antimuscarinic agents for the treatment of neurogenic bladder disease. The compounds disclosed were said to have longer durations of action than did older anticholinergic agents such as methantheline and propantheline. The majority of neurogenic bladder patients have spastic or hypertonic conditions. Clinicians generally aim to convert this condition to hypotonia as a way to treat the primary problem of incontinence. Thus, when the condition has been “converted” to hypotonia, it can be managed in a straightforward way by intermittent catheterization. For those patients who cannot be converted from the hypertonic to the hypotonic state and who still need to urinate every hour, longer term treatment with an anticholinergic drug (muscarinic receptor antagonists) was said to be necessary. As noted above, the current drug of choice for this treatment is oxybutynin which is considered to be better than the older anticholinergics. McPherson et al. (supra) disclosed 1-aryl-1-hydroxy-1-R
1
-3-(4-R
2
-1-piperazinyl)-2-propanones. In preferred compounds, R
1
was a cycloalkyl of 3-6 carbons, most preferably cyclohexyl or cyclobutyl. R
2
was lower alkyl, benzyl, para-substituted benzyl or cinnamyl. The most preferred compound was 1-cyclobutyl-1-hydroxy-1-phenyl-3-(4-benzyl-1-piperazinyl)-2-propanone. For parenteral administration, the compounds were prepared in conventional aqueous injection solutions. This document disclosed that extemporaneous injection solutions could be prepared from sterile pills, granules or tablets and contained diluents, dispersing and surface active agents, binders and lubricants as well as the anticholinergic compound.
Tolterodine is a new antimuscarinic of comparable duration of action which is reported to cause a lower incidence of dry mouth (~9%). The following dose-related side effects were observed with tolterodine: diminished stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and altered the nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg
Other Drugs in the Treatment of Urinary Incontinence
Terodiline has both anticholinergic and calcium antagonist properties, and effectively reduces abnormal bladder contractions caused by detrusor instability (Langtry, HD et al.,
Drugs
40:748-761 (1990)). When administered to adult patients with urge incontinence (generally as a 25 mg dose twice daily), terodiline reduced micturition frequency and incontinence episodes. Bladder volume at first urge and bladder capacity were increased. Children with diurnal enuresis respond similarly to a daily 25 m
Criares Theodore J.
Kim Jennifer
Nixon & Peabody LLP
University of Rochester
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